EP1051415A1 - Benzamidderivate als vasopressin-antagonisten - Google Patents

Benzamidderivate als vasopressin-antagonisten

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Publication number
EP1051415A1
EP1051415A1 EP99900176A EP99900176A EP1051415A1 EP 1051415 A1 EP1051415 A1 EP 1051415A1 EP 99900176 A EP99900176 A EP 99900176A EP 99900176 A EP99900176 A EP 99900176A EP 1051415 A1 EP1051415 A1 EP 1051415A1
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Prior art keywords
salt
compound
tetrahydro
nmr
methoxy
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EP99900176A
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English (en)
French (fr)
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EP1051415B1 (de
Inventor
Hiroyuki Setoi
Takehiko Ohkawa
Yuki Sawada
Kazuhiko Osoda
Teruo Oku
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • vasopressin antagonist for example, in PCT International Publication Nos. WO 91/05549 and WO 95/29152, EP Publication No. 0620216, and Japanese Patent Unexamined Publication Nos. 154765/1992 and 221476/1997.
  • This invention relates to new benzamide derivatives and salts thereof.
  • benzamide derivatives and salts thereof which exhibit activities such as vasopressin antagonistic activity
  • pharmaceutical compositions comprising the same and to methods for the treatment and/or prophylaxis of cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), depressant, anxiety and the like in human beings and animals.
  • cerebrovascular disease e.g. cerebral edema, cerebral infarction, etc.
  • depressant e.g. cerebral edema, cerebral infarction, etc.
  • anxiety and the like in human beings and animals.
  • One object of this invention is to provide new and useful benzamide derivatives and salts thereof which possess the aforesaid activities.
  • Another object of this invention is to provide processes for the preparation of said benzamide derivatives and salts thereof.
  • a further object of this invention is to provide pharmaceutical compositions comprising, as an active ingredient, said benzamide derivatives or pharmaceutically acceptable salts thereof.
  • Still further object of this invention is to provide methods for the treatment and/or prophylaxis of the aforesaid diseases in human beings and animals, using said benzamide derivatives and pharmaceutically acceptable salts thereof.
  • A is an optionally substituted heterocyclic group
  • R is a lower alkoxy
  • B is a saturated or unsaturated condensed ring group selected from the group consisting of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, each member being optionally substituted, preferably, by the following formula (II) :
  • the object compound (I) of the present invention can be prepared according to the following reaction schemes.
  • B 1 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is
  • a 2 is a heterocyclic group not substituted with an N-protective group or substituted with amino or a substituent having amino
  • B 2 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenz- oxazepinyl and indolinyl, which is not substituted with an N-protective group or substituted with amino or a substituent having amino, and Z and R are each as defined above.
  • B* is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with hydroxy
  • A, Z and R are each as defined above.
  • a 3 is a heterocyclic group substituted with phthaloylamino- alkyl
  • A* is a heterocyclic group substituted with aminoalkyl
  • B, Z and R are each as defined above.
  • a 5 is a heterocyclic group substituted with amino or aminoalkyl
  • a 6 is a heterocyclic group substituted with (di)alkylamino or (di)alkylaminoalkyl
  • B, Z and R are each as defined above.
  • a 7 is a heterocyclic group substituted with acylamino or acylaminoalkyl, and A 5 , B, Z and R are each as defined above.
  • a 9 is a heterocyclic group substituted with hydroxyalkyl
  • B, Z and R are each as defined above.
  • B 5 is a saturated or unsaturated benzothiazepinyl
  • B 6 is a saturated or unsaturated S-oxo-benzothiazepinyl
  • A, Z and R are each as defined above.
  • B 7 is a saturated or unsaturated S,S-dioxo-benzothiazepinyl, and A, Z, B 6 and R are each as defined above.
  • Suitable salts of the object compound [I] are pharmaceutically acceptable, conventional non-toxic mono- or di-salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt), an organic acid addition salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt), an organic
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate
  • a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt.
  • lower is intended to mean a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise provided.
  • Suitable "heterocyclic group” defined for A of the formula (I) includes saturated or unsaturated, monocyclic or polycyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. 1H-azepinyl), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g.
  • perhydro-1H-azepinyl pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl (e.g. imidazo[4,5-c]pyridyl), tetrahydroimidazopyridyl (e.g.
  • saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) , for example, thienyl, dihydrodithiinyl, etc. ; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc. ; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s) , for example, dihydrooxathiinyl, etc. ; unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.; and
  • Suitable “substituent(s)" of "heterocyclic group” includes lower alkyl optionally substituted with hydroxy, protected hydroxy, amino, protected amino, alkyl-substituted amino, lower alkoxy, acylamino or N- containing heterocyclic group; N-protective group; lower alkoxy; haloalkyl; amino optionally substituted with lower alkyl, acyl or N- protective group; carbamoyl optionally substituted with lower alkyl; acyl; acylamino; aminoalkylamino optionally substituted with lower alkyl or N-protective group; and N-containing heterocyclic group optionally substituted with lower alkyl, amino optionally substituted with lower alkyl or N-protective group,
  • Suitable "lower alkyl” and “lower alkyl” moiety in “optionally substituted with lower alkyl” include straight or branched (Ci-C ⁇ )- alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-ethylpropyl and hexyl, in which the preferred one is (C.-C alkyl.
  • Suitable "lower alkoxy” and “lower alkoxy” moiety in “optionally substituted with lower alkoxy” include straight or branched (Ci-C ⁇ )- alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 2-ethylpropoxy and hexoxy, in which the preferred one is (Ci-C alkoxy.
  • N-protective group in “optionally substituted with N-protective group” and amino-protective group of "a protected amino”
  • aryl(lower)alkyl such as mono- or di- or triphenyKlower)alkyl (e.g. benzyl, phenethyl, 1- phenylethyl, benzhydryl, trityl) and acyl as explained hereinbelow.
  • Suitable "acyl”, “acyl” moiety in “optionally substituted with acyl or acylamino” and “acyl” moiety in “acylamino” include aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from caboxylic acid, carbonic acid, carbamic acid or sulfonic acid.
  • Suitable examples of the acyl group thus explained are lower alkanoyl (e.g. formyl, acetyl, propionyl, hexanoyl, pivaloyl), mono(or di or tri)halo(lower)alkanoyl (e.g. chloroacetyl, trifluoroacetyl) , lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl) , mono(or di or tri)halo(lower)alkoxycarbonyl (e.g.
  • lower alkanoyl e.g. formyl, acetyl, propionyl, hexanoyl, pivaloyl
  • mono(or di or tri)halo(lower)alkanoyl e.g. chloroacetyl, triflu
  • chloromethoxycarbonyl dichloroethoxycarbonyl, trichloroethoxycarbonyl
  • aroyl e.g. benzoyl, toluoyl, xyloyl, naphthoyl
  • aryl(lower)alkanoyl such as phenyl- (lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl)
  • aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl
  • aryloxy(lower)alkanoyl such as phenoxy(lower)alkanoyl (e.g.
  • phenoxyacetyl, phenoxypropionyl) , arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl), aryl(lower)alkoxycarbonyl which may have suitable substituent(s) such as phenyKlower)alkoxycarbonyl which may have nitro or lower alkoxy (e.g.
  • benzyloxycarbonyl phenethyloxycarbonyl, p-nitrobenzyloxy- carbonyl, p-methoxybenzyloxycarbonyl) , thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, triazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, lower alkylsulfonyl (e.g.
  • arylsulfonyl e.g. phenylsulfonyl, tolylsufonyl, xylylsufonyl, naphth
  • Examples of preferable "protected amino” are aryl(lowe )- alkylamino, lower alkanoylamino and lower alkoxycarbonyl- amino, more preferable ones are triphenyMC.-Ct.)alkylamino, (Ci -Ct. )— alkanoylamino and (C ⁇ -Cu)alkoxycarbonylamino, and the most preferable ones are tritylaino, formamido, acetamido and tert-butoxycarbonyl- amino.
  • alkyl moiety in “alkyl-substituted amino", “haloalkyl” and “aminoalkylamino” include straight or branched (C ⁇ -Ce)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
  • alkyl-substituted amino examples include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino, dipentylamino, dihexylamino or the like.
  • haloalkyl examples include fluoro ethyl, 1- fluoroethyl, 2-fluoroethyl, 1-fluoropropyl, 2-fluoropropyl, 3- fluoropropyl, 4-fluorobutyl, 5-fluoropentyl, 6-fluorohexyl, chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2- chloropropyl, 3-chloropropyl, 4-chlorobutyl, 5-chloropentyl, 6- chlorohexyl, bromomethyl, 1-bromoethyl, 2-bromoethyl, 1-bromopropyl, 2-bromopropyl, 3-bromopropyl, 4-bromobutyl, 5-bromopentyl, 6- bromohexyl, iodomethyl, 1-iodoethyl, 2-iodoethyl
  • aminoalkylamino and “aminoalkylamino” moiety in “optionally substituted with aminoalkylamino” are aminomethylamino, aminoethylamino, aminopropylamino, aminoisopropyl ⁇ amino, aminobutylamino, aminoisobutylamino, amino-tert-butylamino, aminopentylamino, aminohexylamino, di(aminomethyl)amino, di(aminoethyl)amino, di(aminopropyl)amino, di(aminoisopropyl)amino, di(aminobutyl)amino, di(aminoisobutyl)amino, di(amino-tert-butyl)- amino, di(aminopentyl)amino, di(aminohexyl)amino or the like.
  • N-containing heterocyclic group and “N-containing heterocyclic group” moiety in “optionally substituted with N- containing heterocyclic group” include ones containing N atom(s) from among those exemplified above with regard to "heterocyclic group”.
  • Suitable "protected hydroxy" includes hydroxy protected by a
  • substituted lower alkoxy such as lower alkoxy(lower)alkoxy (e.g. methoxymethoxy) , lower alkoxy(lower)alkoxy(lower)alkoxy (e.g. methoxyethoxymethoxy) and substituted or unsubstituted aryl(lower)alkoxy (e.g. benzyloxy, nitrobenzyloxy) ; acyloxy such as lower alkanoyloxy (e.g. acetoxy, propionyloxy, pivaloyloxy) , aroyloxy (e.g.
  • Examples of preferable "heterocyclic group" defined for A of the formula (I) are substituted or unsubstituted 1H-benzimidazol-4-yl such as 2-methyl-1-tert-butoxycarbonyl-1H-benzimidazol-4-yl, 2-methyl-1H- benzimidazol-4-yl, 2-phthaloylaminomethyl-1H-benzimidazol-4-yl, 2- aminomethyl-1H-benzimidazol-4-yl, 2-dimethylaminomethyl-1 H- benzimidazol-4-yl, 2-methanesulfonylaminomethyl-1 H-benzimidazol-4-yl, 2-(morpholin-4-yl)methyl-1H-benzimidazol-4-yl, 2-(4-tert-butoxy- carbonylpiperazin-1 -yl) ethyl-1H-benzimidazol-4-yl, 2-(piperazin-1 -yl) methyl-1H-benzimida
  • Condensed ring group defined for B of the formula (I) may be saturated or unsaturated.
  • Unsaturated condensed ring group includes partly unsaturated condensed ring group.
  • Suitable "lower alkyl” and “N-protective group” are the same as those defined above with regard to the substituents of "heterocyclic group”.
  • Suitable "halogen” includes fluoro, chloro, bromo and iodo.
  • unsaturated benzodiazepinyl such as 2,3,4,5 ⁇ tetrahydro-4-oxo-1H- 1 ,5-benzodiazepin-1 -yl, 2,3,4,5-tetrahydro-5-oxo-1H-1 ,4-benzodiazepin- 1 ⁇ yl » 3-methy1-4-0X0-2,3,4,5-tetrahydro-1H-1 ,3-benzodiazepin-1 -yl and 4-methyl- ,3,4, 5-tetrahydro-1H-1 ,4-benzodiazepin-1 -yl; unsaturated pyridoazepinyl such as 6,7,8,9-tetrahydro-5H- pyrido[2,3-b]azepin-9-yl, 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-1- yl, 2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-1-
  • the object compound (I) or a salt thereof can be prepared by reacting a compound (III) or its reactive derivative at the carboxyl group or a salt thereof, with a compound (IV) or its reactive derivative at the amino group or a salt thereof.
  • Suitable salts of the compounds (III) and (IV) may be the same as those exemplified above with regard to the compound (I).
  • Suitable reactive derivative at the carboxy group of the compound (III) includes an acid halide, an acid anhydride, an activated amide and an activated ester.
  • suitable reactive derivatives may be an acid chloride; an acid azide", a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid), aliphatic carboxylic acid (e.g.
  • acetic acid propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid), or aromatic carboxylic acid (e.g. benzoic acid); a symmetrical acid anhydride * , an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1 -hydroxy-1H-benzotriazole; or an activated ester (e.g.
  • Suitable salts of the compound (III) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
  • Suitable reactive derivative at the amino group of the compound (IV) includes Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IV) with a carbonyl compound such as aldehyde or ketone", a silyl derivative formed by the reaction of the compound (IV) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide or bis(trimethylsilyl)urea; and a derivative formed by reaction of the compound (IV) with phosphorus trichloride or phosgene.
  • Suitable salts of the compound (IV) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
  • the reaction is usually carried out in a conventional solvent such as water, an alcohol (e.g. methanol, ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, N,N- dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, an alcohol (e.g. methanol, ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, N,N- dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, an alcohol (e.g. methanol, ethanol), acetone
  • the reaction when the compound (III) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'- dicyclohexylcarbodiimide; N-cyclohexyl-N' -morpholinoethylcarbodiimide; N-cyclohexyl-N' -(4-diethylaminocyclohexyl)carbodiimide; N,N' - diethylcarbodiimide", N,N' -diisopropylcarbodiimide; N-ethyl-N' -(3- dimethylaminopropyDcarbodiimide; N,N' -carbonylbis-(2- methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene", 1
  • the reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal carbonates, alkali metal hydrogencarbonates, tri(lower)alkylamine, pyridide, N-(lower)- alkylmorpholine or N,N-di(lower)alkylbenzylamine.
  • an inorganic or organic base such as alkali metal carbonates, alkali metal hydrogencarbonates, tri(lower)alkylamine, pyridide, N-(lower)- alkylmorpholine or N,N-di(lower)alkylbenzylamine.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the object compound (lb) or a salt thereof can be prepared by subjecting a compound (la) or a salt thereof to elimination reaction of the N-protective group in A 1 and/or B 1 .
  • This reaction is carried out in accordance with a conventional method such as hydrolysis or reduction.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base includes, for example, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate) ; and organic bases such as trialkylamines (e.g. trimethylamine, triethylamine) ,
  • Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid) .
  • organic acids e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid
  • inorganic acids e.g. hydrochloric acid, hydrobromic acid, sulfuric acid
  • Lewis acid such as trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid) is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol).
  • cation trapping agents e.g. anisole, phenol
  • the reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, an alcohol (e.g. methanol, ethanol), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming
  • the reaction method applicable to the elimination reaction includes chemical reduction and catalytic reduction.
  • Suitable reducing agent to be used in chemical reduction is a combination of a metal (e.g. tin, zinc, iron) or metallic compound (e.g. chromium chloride, chromium acetate) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid).
  • a metal e.g. tin, zinc, iron
  • metallic compound e.g. chromium chloride, chromium acetate
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid.
  • Suitable salts of the compounds (Ic) and (Id) may be the same as those exemplified above with regard to the compound (I).
  • Suitable salts of the compounds (le) and (If) may be the same as
  • This reaction is carried out in accordance with a conventional method using a base or an acid including Lewis acid.
  • Suitable base includes an inorganic or organic base such as alkaline metals (e.g. sodium, potassium), alkaline earth metals (e.g. magnesium, calcium), hydrides thereof, hydroxides thereof, carbonate salts thereof, bicarbonate salts thereof, alkylamine (e.g. methylamine, trimethylamine, triethylamine) , picoline, 1,5- diazabicyclo[4.3.0]non-5-ene, 1 ,4-diazabicyclo[2.2.2]octane, 1,8- diazabicyclo[5.4.0]undec-7-ene.
  • alkaline metals e.g. sodium, potassium
  • alkaline earth metals e.g. magnesium, calcium
  • hydrides thereof hydroxides thereof
  • carbonate salts thereof e.g. calcium
  • bicarbonate salts thereof e.g. methylamine, trimethylamine, triethylamine
  • alkylamine e.g. methylamine, trimethylamine
  • Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid), inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride) and acid addition salt compounds (e.g. pyridine hydrochloride) .
  • organic acids e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid
  • inorganic acids e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride
  • acid addition salt compounds e.g. pyridine hydrochloride
  • the object compound (Ih) or a salt thereof can be prepared by reacting a compound (Ig) or a salt thereof with an alkylating agent.
  • Suitable salts of the compounds (Ig) and (Ih) may be the same as those exemplified above with regard to the compound (I).
  • This reaction is carried out in accordance with a conventional method using a conventional alkylating agent.
  • the reaction may preferably be carried out in the presence of alkaline metals (e.g. sodium, potassium), alkaline earth metals (e.g. magnesium, calcium), hydride thereof, hydroxide thereof, carbonate salts thereof, bicarbonate salts thereof, and organic base (e.g. tri(lower)alkylamine, N,N-di(lower)alkylaniline) .
  • alkaline metals e.g. sodium, potassium
  • alkaline earth metals e.g. magnesium, calcium
  • the object compound (Ii) or a salt thereof can be prepared by reacting a compound (Ig) or a salt thereof with an acylating agent.
  • This reaction is carried out in accordance with a conventional method using a conventional acylating agent.
  • Suitable acylating agent includes an organic acid represented by the formula: R'-OH wherein R' is acyl or substituted acyl as illustrated above, or its reactive derivative.
  • Suitable organic acid derivative includes conventional ones such as acid halides (e.g. acid chlorides, acid bromides), acid azides, acid anhydrides, activated amides and activated esters.
  • acid halides e.g. acid chlorides, acid bromides
  • acid azides e.g. acid anhydrides
  • activated amides e.g. activated esters.
  • acylating agent in a free acid form or its salt form, the acylation may preferably be carried out in the presence of a conventional condensing agent as explained in Process 1.
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, acetone, dioxane, chloroform, methylene chloride, acetonitrile, ethylene chloride, tetrahydrofuran, acetic acid, N,N-dimethylform- amide, pyridine, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction, such as water, acetone, dioxane, chloroform, methylene chloride, acetonitrile, ethylene chloride, tetrahydrofuran, acetic acid, N,N-dimethylform- amide, pyridine, or a mixture thereof.
  • reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
  • the object compound (Ik) or a salt thereof can be prepared by subjecting a compound (Ij) or a salt thereof to elimination reaction of the hydroxy-protective group in A 8 .
  • Suitable salts of the compounds (Ij) and (Ik) may be the same as those exemplified above with regard to the compound (I).
  • reaction can be carried out in substantially the same manner as in Process 2, and therefore, the reaction mode and reaction conditions (e.g. base, acid, catalyst, solvent, reaction temperature) of this reaction are to be referred to those explained in Process 2.
  • reaction mode and reaction conditions e.g. base, acid, catalyst, solvent, reaction temperature
  • the object compound (Im) or a salt thereof can be prepared by subjecting a compound (II) or a salt thereof to oxidation of S atom
  • the object compound (In) or a salt thereof can be prepared by subjecting a compound (Im) or a salt thereof to oxidation of S atom in B 6 .
  • Suitable salts of the compounds (II), (Im) and (In) may be the same as those exemplified above with regard to the compound (I).
  • This reaction is carried out in accordance with a conventional method using an oxidizing agent.
  • Suitable oxidizing agent includes hydrogen peroxide, Jones reagent, peracids (e.g. peracetic acid, perbenzoic acid, m- chloroperbenzoic acid), chromic acid, potassium permanganate, and alkali metal periodates (e.g. sodium periodate).
  • peracids e.g. peracetic acid, perbenzoic acid, m- chloroperbenzoic acid
  • chromic acid chromic acid
  • potassium permanganate e.g. sodium periodate
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, organic acid (e.g. acetic acid, trifluoroacetic acid), acetone, ethyl acetate, alcohol (e.g. methanol, ethanol), dichloromethane, chloroform, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction, such as water, organic acid (e.g. acetic acid, trifluoroacetic acid), acetone, ethyl acetate, alcohol (e.g. methanol, ethanol), dichloromethane, chloroform, or a mixture thereof.
  • the object compound (I) thus obtained can be converted to a pharmaceutically acceptable salt in a conventional manner.
  • the object compound (I) may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) or double bond(s), and all such isomers and mixtures thereof are included within the scope of this invention.
  • the object compound (I) and pharmaceutically acceptable salts of the present invention exhibit activities such as vasopressin
  • hypertension heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome,
  • Test 1 In order to illustrate the usefulness of the object compound (I), the pharmacological data of the compound (I) are shown in the following. Test 1
  • V1 Vasopressin 1 receptor binding
  • Vasopressin 2 (V2) receptor binding (i) Test Method
  • the dosage of the compound (I) or pharmaceutically acceptable salts threrof will vary depending upon the age and condition of patients, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg or 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

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EP99900176A 1998-01-27 1999-01-11 Benzamidderivate als vasopressin-antagonisten Expired - Lifetime EP1051415B1 (de)

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AUPP150098 1998-01-27
AUPP1500A AUPP150098A0 (en) 1998-01-27 1998-01-27 Benzamide derivatives
PCT/JP1999/000072 WO1999037637A1 (en) 1998-01-27 1999-01-11 Benzamide derivatives as vasopressin antagonists

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EP1226132A1 (de) * 1999-11-04 2002-07-31 Ortho-McNeil Pharmaceutical, Inc. Nichtpeptide substituierte benzothiazepine als vasopressin-antagonisten
HUP0301590A3 (en) * 2000-07-05 2005-01-28 Ortho Mcneil Pharm Inc Nonpeptide substituted spirobenzoazepines as vasopressin antagonists, pharmaceutical compositions containing them and their preparation
EP1567497B1 (de) * 2002-12-06 2009-09-23 Purdue Research Foundation Pyridine zur behandlung von verletztemsäugetiernervengewebe
ES2332724T3 (es) 2003-06-17 2010-02-11 Janssen Pharmaceutica Nv Espirobenzoazepinas sustituidas.
GB0330042D0 (en) 2003-12-24 2004-01-28 Pharmacia Italia Spa Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions them
GB0330043D0 (en) 2003-12-24 2004-01-28 Pharmacia Italia Spa Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions comprising them
AR051780A1 (es) * 2004-11-29 2007-02-07 Japan Tobacco Inc Compuestos en anillo fusionados que contienen nitrogeno y utilizacion de los mismos
DE102005012873B4 (de) * 2005-03-19 2007-05-03 Sanofi-Aventis Deutschland Gmbh Aminocarbonyl substituierte 8-N-Benzimidazole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
PT1912976E (pt) * 2005-07-21 2009-01-07 Hoffmann La Roche Derivados de indol-3-il-carboni-piperidin-benzimidazole como antagonistas dos receptores v1a
US7741317B2 (en) * 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
CA2643802A1 (en) * 2006-02-27 2007-09-07 Alexander Michalow Methods for regulating neurotransmitter systems by inducing counteradaptations
US20080064871A1 (en) * 2006-05-26 2008-03-13 Japan Tobacco Inc. Production Method of Nitrogen-Containing Fused Ring Compounds
US20080305169A1 (en) * 2006-05-26 2008-12-11 Japan Tobacco Inc. Pharmaceutical Compositions Comprising Nitrogen-Containing Fused Ring Coumpounds
JP4108729B2 (ja) * 2006-05-26 2008-06-25 日本たばこ産業株式会社 窒素含有縮合環化合物含有医薬組成物
AU2007299822A1 (en) 2006-09-22 2008-03-27 Janssen Pharmaceutica N.V. Spiro benzazepines as vasopressin antagonists
PL2078022T3 (pl) 2006-09-22 2012-04-30 Janssen Pharmaceutica Nv Spirobenzoazepiny stosowane jako antagoniści wazopresyny
WO2019003433A1 (ja) 2017-06-30 2019-01-03 大塚製薬株式会社 ベンゾアゼピン誘導体
JP6868089B2 (ja) * 2018-12-28 2021-05-12 大塚製薬株式会社 医薬

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ATE250599T1 (de) 2003-10-15
AUPP150098A0 (en) 1998-02-19
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DE69911580T2 (de) 2004-04-22

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